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1.
PLoS Biol ; 18(3): e3000688, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32218572

RESUMO

Obesity leads to multiple health problems, including diabetes, fatty liver, and even cancer. Here, we report that urolithin A (UA), a gut-microflora-derived metabolite of pomegranate ellagitannins (ETs), prevents diet-induced obesity and metabolic dysfunctions in mice without causing adverse effects. UA treatment increases energy expenditure (EE) by enhancing thermogenesis in brown adipose tissue (BAT) and inducing browning of white adipose tissue (WAT). Mechanistically, UA-mediated increased thermogenesis is caused by an elevation of triiodothyronine (T3) levels in BAT and inguinal fat depots. This is also confirmed in UA-treated white and brown adipocytes. Consistent with this mechanism, UA loses its beneficial effects on activation of BAT, browning of white fat, body weight control, and glucose homeostasis when thyroid hormone (TH) production is blocked by its inhibitor, propylthiouracil (PTU). Conversely, administration of exogenous tetraiodothyronine (T4) to PTU-treated mice restores UA-induced activation of BAT and browning of white fat and its preventive role on high-fat diet (HFD)-induced weight gain. Together, these results suggest that UA is a potent antiobesity agent with potential for human clinical applications.


Assuntos
Tecido Adiposo Marrom/metabolismo , Fármacos Antiobesidade/uso terapêutico , Cumarínicos/uso terapêutico , Obesidade/prevenção & controle , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/prevenção & controle , Intolerância à Glucose/prevenção & controle , Resistência à Insulina , Reação de Maillard , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , Propiltiouracila/toxicidade , Termogênese , Tri-Iodotironina/antagonistas & inibidores , Tri-Iodotironina/metabolismo , Ganho de Peso/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-31672575

RESUMO

Schizophrenia is a neuropsychiatric disorder that chronically affects 21 million people worldwide. Second-generation antipsychotics (SGAs) are the cornerstone in the management of schizophrenia. However, despite their efficacy in counteracting both positive and negative symptomatology of schizophrenia, recent clinical observations have described an increase in the prevalence of metabolic disturbances in patients treated with SGAs, including abnormal weight gain, hyperglycemia and dyslipidemia. While the molecular mechanisms responsible for these side-effects remain poorly understood, increasing evidence points to a link between SGAs and adipose tissue depots of white, brown and beige adipocytes. In this review, we survey the present knowledge in this area, with a particular focus on the molecular aspects of adipocyte biology including differentiation, lipid metabolism, thermogenic function and the browning/beiging process.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Antipsicóticos/efeitos adversos , Síndrome Metabólica/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Clozapina/efeitos adversos , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/fisiologia , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/metabolismo , Prevalência , Esquizofrenia/metabolismo , Fatores Sexuais , Termogênese/efeitos dos fármacos
3.
Planta Med ; 86(1): 45-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31663108

RESUMO

A previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of Sargassum serratifolium (MES) stimulated adipose tissue browning and inhibited diet-induced obesity and metabolic syndrome. Sargaquinoic acid (SQA) is a major component in MES. We investigated the effects of SQA on the differentiation of preadipocytes to the beige adipocytes. SQA was treated in 3T3-L1 adipocytes differentiated under a special condition that has been reported to induce the browning of adipocytes. SQA at 10 µM reduced lipid accumulation by approximately 23%. SQA at 2.5 - 10 µM induced the differentiation of white adipocytes to beige adipocytes partially by increasing the mitochondrial density and the expression of beige/brown adipocyte markers. In addition, SQA activated lipid catabolic pathways, evidenced by the increased expression levels of perilipin, carnitine palmitoyltransferase 1, and acyl-CoA synthetase long-chain family member 1. As a partial mechanism, biochemical and in silico analyses indicate that SQA activated AMP-activated protein kinase signaling in adipocytes.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Alcenos/farmacologia , Benzoquinonas/farmacologia , Sargassum/química , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/citologia , Alcenos/isolamento & purificação , Alcenos/toxicidade , Animais , Benzoquinonas/isolamento & purificação , Benzoquinonas/toxicidade , Camundongos , Transdução de Sinais/efeitos dos fármacos
4.
J Agric Food Chem ; 67(51): 14056-14065, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31789021

RESUMO

The main purpose of the present study was to investigate the browning effect of 6-gingerol (6G), one of the main functional compounds in the ethyl acetate extract of ginger (ginger ethyl acetate fraction, GEF), and its underlying mechanisms. In this study, we first discovered that GEF stimulated brown adipocyte differentiation by upregulating the expression levels of browning-specific transcription makers (UCP1, PRDM16, and PGC-1α), thereby reducing lipogenesis transcriptional regulator (C/EBPα) expression in 3T3-L1-differentiated adipocytes. Then, 6G (47.81 ± 0.62 mg/g) was identified as one of the main functional compounds in GEF using high-performance liquid chromatography. 6G promoted adipocyte browning, as evidenced by an increase in some brown/beige fat-specific genes (PGC-1α, Cidea, Prdm16, Cited1, SIRT1, Tmem26, and Ucp1) and proteins (UCP1, CEBP/ß, PGC-1α, and PRDM16) expression levels. Moreover, 6G greatly improved mitochondrial respiration and energy metabolism by upregulating the expression levels of some mitochondrial biogenesis markers (Tfam, Nrf1, SIRT1, and p-AMPK/AMPK) and increasing the uncoupled oxygen consumption rate of protons leaked in 3T3-L1 cells. Comparison of the experimental results obtained with an inhibitor (dorsomorphin) and an activator (5-aminoimidazole-4-carboxamide ribonucleotide) suggested that the 6G-associated regulation of the energy metabolism effect was mediated partly through the AMPK signaling pathway. This study provides new insight into the promotion of fat browning and regulation of lipid metabolism by 6G and suggests that 6G likely has potential therapeutic effects on obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/efeitos dos fármacos , Catecóis/farmacologia , Álcoois Graxos/farmacologia , Gengibre/química , Extratos Vegetais/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipócitos Marrons/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Camundongos , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
5.
Nutrients ; 11(11)2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31731817

RESUMO

It is well known that perivascular fat tissue (PVAT) dysfunction can induce endothelial cell (EC) dysfunction, an event which is related with various cardiovascular diseases. In this study, we evaluated whether Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB), one component of ECE, could attenuate EC dysfunction by modulating diet-induced PVAT dysfunction mediated by inflammation and ER stress. A high fat diet (HFD) led to an increase in the number and size of white adipocytes in PVAT; PPB and ECE attenuated those increases. Additionally, ECE and PPB attenuated: (i) an increase in the number of M1 macrophages and the expression level of monocyte chemoattractant protein-1 (MCP-1), both of which are related to increases in macrophage infiltration and induction of inflammation in PVAT, and (ii) the expression of pro-inflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, chemerin) in PVAT which led to vasoconstriction. Furthermore, ECE and PPB: (i) enhanced the expression of adiponectin and IL-10 which had anti-inflammatory and vasodilator effects, (ii) decreased HFD-induced endoplasmic reticulum (ER) stress and (iii) attenuated the ER stress mediated reduction in sirtuin type 1 (Sirt1) and peroxisome proliferator-activated receptor γ (PPARγ) expression. Protective effects against decreased Sirt1 and PPARγ expression led to the restoration of uncoupling protein -1 (UCP-1) expression and the browning process in PVAT. PPB or ECE attenuated endothelial dysfunction by enhancing the pAMPK-PI3K-peNOS pathway and reducing the expression of endothelin-1 (ET-1). In conclusion, PPB and ECE attenuated PVAT dysfunction and subsequent endothelial dysfunction by: (i) decreasing inflammation and ER stress, and (ii) modulating brown adipocyte function.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Células Endoteliais/efeitos dos fármacos , Doenças Vasculares Periféricas/tratamento farmacológico , Feófitas , Extratos Vegetais/farmacologia , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Animais , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dioxinas/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Vasculares Periféricas/etiologia , Floroglucinol/farmacologia , Pirogalol/farmacologia
6.
Obesity (Silver Spring) ; 27(12): 2018-2024, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31674727

RESUMO

OBJECTIVE: Serotonin was shown to interfere with the differentiation of brown adipocytes. In addition, clock components inhibit brown adipogenesis through direct transcriptional control of key components of the transforming growth factor ß pathway. The aim of this study was to investigate whether serotonin abrogates brown adipogenesis by affecting clock functionality. METHODS: Nondifferentiated and differentiated HIB1B brown adipocytes were treated with serotonin, and their clock expression and functionality and differentiation state were examined. RESULTS: Nondifferentiated HIB1B brown adipocytes treated with serotonin showed increased brown adipocyte markers alongside increased brain-muscle Arnt-like protein 1 (Bmal1) and RAR related orphan receptor A (Rora) but decreased nuclear receptor Rev-erbα mRNA levels. BMAL1 overexpression together with serotonin led to significantly lower brown adipocyte markers. Serotonin in the differentiation cocktail led to reduced brown adipocyte markers as well as clock gene expression. After differentiation, serotonin treatment significantly decreased brown adipocyte markers and reduced BMAL1 and RORα but increased REV-ERBα protein levels. Addition of serotonin to the differentiation medium or addition after differentiation reduced activity of calcium/calmodulin-dependent protein kinase type II subunit gamma, which interferes with circadian locomoter output cycles protein kaput (CLOCK):BMAL1 dimerization and transactivation. CONCLUSIONS: Clock expression is required at the early stages of differentiation to brown adipocytes, and serotonin interferes with this process by modulating clock functionality. Serotonin interferes with clock functionality by reducing the levels of the active form of calcium/calmodulin-dependent protein kinase type II subunit gamma.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Relógios Circadianos/fisiologia , Serotonina/uso terapêutico , Diferenciação Celular , Humanos , Serotonina/farmacologia
7.
J Food Sci ; 84(12): 3815-3824, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31750946

RESUMO

Brown adipose tissue (BAT) prevents obesity and related diseases by uncoupling oxidative phosphorylation with adenosine triphosphate. Previous studies have demonstrated that polyphenols can promote the thermogenesis of BAT in mice. Chlorogenic acid (CGA) is a common phenolic acid found in fruits and vegetables, as well as traditional Chinese medicine, which is responsible for a variety of physiological activities. However, it is still unclear whether CGA has positive effects on the thermogenesis of BAT. In this study, CGA enhances the thermogenesis and proton leak of brown adipocytes, however, no changes are evident regarding the differentiation of C3 H10 T1/2 into brown adipocytes. Surprisingly, CGA promotes the uptake of glucose by upregulating the glucose transporter 2 and phosphofructokinase. Moreover, CGA increases the number and the function of mitochondrial. Taken together, CGA stimulates thermogenesis of brown adipocytes by promoting the uptake of glucose and the function of mitochondria. PRACTICAL APPLICATION: Chlorogenic acid (CGA) is widely found in fruits, vegetables, and traditional Chinese medicines, which has been considered to have antibacterial and anti-inflammatory function. However, whether it has the function of resisting obesity and promoting thermogenesis is still unclear. In this study, brown adipocyte was used to explore the function and mechanism of CGA on thermogenesis. It provides new ideas for the utilization of foods rich in CGA and traditional Chinese medicine.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Ácido Clorogênico/farmacologia , Glucose/metabolismo , Mitocôndrias/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Animais , Camundongos
8.
Nutrients ; 11(11)2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31726767

RESUMO

In this study, we investigated the effects of black ginseng (BG) and ginsenoside Rb1, which induced browning effects in 3T3-L1 and primary white adipocytes (PWATs) isolated from C57BL/6 mice. BG and Rb1 suppressed the expressions of CCAAT/enhancer-binding protein alpha (C/EBPα) and sterol regulatory element-binding transcription factor-1c (SREBP-1c), whereas the expression level of peroxisome proliferator-activated receptor gamma (PPARγ) was increased. Furthermore, BG and Rb1 enhanced the protein expressions of the brown-adipocyte-specific markers PR domain containing 16 (PRDM16), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and uncoupling protein 1 (UCP1). These results were further supported by immunofluorescence images of mitochondrial biogenesis. In addition, BG and Rb1 induced expressions of brown-adipocyte-specific marker proteins by AMP-activated protein kinase (AMPK) activation. BG and Rb1 exert antiobesity effects by inducing browning in 3T3-L1 cells and PWATs through AMPK-mediated pathway activation. We suggest that BG and Rb1 act as potential functional antiobesity food agents.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Ginsenosídeos/farmacologia , Panax , Extratos Vegetais/farmacologia , Proteína Desacopladora 1/metabolismo , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Biogênese de Organelas , PPAR gama/metabolismo , Panax/química , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/isolamento & purificação , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo , Regulação para Cima
9.
J Nutr Sci Vitaminol (Tokyo) ; 65(4): 328-334, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474682

RESUMO

Classical brown adipocytes, characterized by interscapular depots, have multilocular fat depots and are known to release excess energy. Recent studies have shown that induction of brown-like adipocytes, also referred to as beige or brite cells, in white adipose tissue (WAT) results in the release of excess energy through mitochondrial heat production via uncoupling protein 1. This has potential a therapeutic strategy for obesity and related diseases as well as classical brown adipocytes. In our previous studies, we found that artepillin C (ArtC, 10 mg/kg body weight), a characteristic constituent of Brazilian propolis, significantly induced the development of brown-like adipocytes in inguinal WAT (iWAT) of mice. Furthermore, we recently demonstrated that curcumin (Cur, 4.5 mg/kg) also significantly induced the development of brown-like adipocytes in mice. The combined administration of several food-derived factors can enhance their bioactivity and reduce their required functional doses. In this study, we showed that co-administration of Cur and ArtC at lower doses (Cur, 1.5 mg/kg; ArtC, 5 mg/kg) additively induce brown-like adipocyte development in mouse iWAT. Moreover, this induction is associated with the localized production of norepinephrine following accumulation of alternatively activated macrophages in iWAT. These findings suggest that co-administration of Cur and ArtC is significantly effective to reduce the dose and enhance the formation of brown-like adipocyte via a unique molecular mechanism.


Assuntos
Adipócitos Marrons/fisiologia , Curcumina/administração & dosagem , Macrófagos/metabolismo , Norepinefrina/biossíntese , Fenilpropionatos/administração & dosagem , Adipócitos Marrons/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Compostos Fitoquímicos/administração & dosagem , Própole/química
10.
Phytomedicine ; 64: 153075, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31476558

RESUMO

BACKGROUND: Obesity is one of the major health problems worldwide. The induction of brown adipocyte formation and activity represents a promising therapeutic option by increasing energy expenditure. Asian herbs have the potential to treat obesity, however, pharmacological effects should be well documented at the molecular level first. HYPOTHESIS: A novel hypothesis-driven screening approach identified the root of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep (PLR) to have potential effects on obesity by stimulating brown adipocytes. STUDY DESIGN: This study explored the metabolic effects of PLR water extract (PLRE) in a high-fat diet-induced obesity mouse model and characterized its secondary metabolite composition. METHODS: Animals were orally treated daily for two weeks and the bioactivity of PLRE evaluated by measuring various parameters including body weight, circulating metabolites, energy expenditure and insulin sensitivity. The chemical composition of the mains components was obtained by HPLC-MS-ELSD-PDA. Based on the dereplication results and semi-quantitative estimation, pure molecules were selected for tests on adipocytes in vitro. RESULTS: PLRE induces brown adipocyte activity and triggers the formation of brown-like cells in inguinal fat tissue, weight loss, and improved glucose metabolism. These effects are primarily caused by cell-autonomous activation of brown adipocytes and not by autonomic nervous system regulation. Even though the analysis of PLRE revealed puerarin as the most abundant secondary metabolite, it showed no effect on brown adipocyte formation and function. Brown adipocyte activity was induced dose-dependently by two other isoflavones, daidzein, and genistein. Daidzein is present in a very small amount in PLRE, but various glycosidic isoflavones, including puerarin, may release daidzein after metabolism. CONCLUSION: This approach demonstrated the positive effects of PLRE on a diet-induced obesity mouse model and provided clues on the mode of action of PLRE at the molecular level.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Pueraria/química , Adipócitos/efeitos dos fármacos , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Animais , Fármacos Antiobesidade/química , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Genisteína/farmacologia , Resistência à Insulina , Isoflavonas/farmacologia , Camundongos , Obesidade/etiologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Pueraria/metabolismo
11.
Nutrients ; 11(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443565

RESUMO

Obesity is a global health threat. Herein, we evaluated the underlying mechanism of anti-obese features of bitter orange (Citrus aurantium Linné, CA). Eight-week-administration of CA in high fat diet-induced obese C57BL/6 mice resulted in a significant decrease of body weight, adipose tissue weight and serum cholesterol. In further in vitro studies, we observed decreased lipid droplets in CA-treated 3T3-L1 adipocytes. Suppressed peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha indicated CA-inhibited adipogenesis. Moreover, CA-treated primary cultured brown adipocytes displayed increased differentiation associated with elevation of thermogenic factors including uncoupling protein 1 and PPARγ coactivator 1 alpha as well. The effects of CA in both adipocytes were abolished in AMP-activated protein kinase alpha (AMPKα)-suppressed environments, suggesting the anti-adipogenic and pro-thermogenic actions of CA were dependent on AMPKα pathway. In conclusion, our results suggest CA as a potential anti-obese agent which regulates adipogenesis and thermogenesis via AMPKα.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Citrus , Dieta Hiperlipídica , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Termogênese/efeitos dos fármacos , Células 3T3-L1 , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/enzimologia , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/enzimologia , Tecido Adiposo/enzimologia , Tecido Adiposo/fisiopatologia , Animais , Fármacos Antiobesidade/isolamento & purificação , Citrus/química , Modelos Animais de Doenças , Ativação Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/enzimologia , Obesidade/fisiopatologia , Extratos Vegetais/isolamento & purificação , Transdução de Sinais
12.
Eur J Pharmacol ; 861: 172596, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31401157

RESUMO

Browning of white adipocytes is considered as a new strategy for the treatment of obesity and its related metabolic diseases. Based on the recent finding that casein kinase-2 (CK2) acts as a negative regulator of browning, new CK2 inhibitors were investigated as potential browning agents. This led to the identification of clomiphene as a candidate. Clomiphene was found to inhibit CK2 activity with an IC50 of 2.39 µM. Accordingly, clomiphene increased mRNA and protein expression of browning markers, including uncoupling protein-1 (UCP1) in 3T3-L1 white adipocytes and in murine primary adipocytes. In agreement with the increased expression of browning markers, reduced lipid droplets, increased oxygen consumption rates, and mitochondrial biogenesis were detected after clomiphene treatment. Furthermore, phosphorylation of histone deacetylase (HDAC) 1 and 2, downstream mediators of CK2 actions, was decreased by clomiphene. On the other hand, CK2 overexpression diminished clomiphene-induced mitochondrial biogenesis as well as expression of browning markers, suggesting that clomiphene-induced browning is related to its inhibition of CK2. In vivo administration of clomiphene increased the mRNA expression of browning markers in various adipose tissues, accompanied by reduced fat weights and body weights in mice. In summary, these data suggested that clomiphene induced the browning of white adipocytes via CK2 inhibition, which may implicate it as a new anti-obesity drug.


Assuntos
Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/citologia , Adipócitos Brancos/efeitos dos fármacos , Caseína Quinase II/antagonistas & inibidores , Clomifeno/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Células 3T3 , Adipócitos Brancos/metabolismo , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosforilação/efeitos dos fármacos
13.
Acta Pharmacol Sin ; 40(12): 1523-1531, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31235818

RESUMO

Unlike white adipose tissue (WAT), brown adipose tissue (BAT) is mainly responsible for energy expenditure via thermogenesis by uncoupling the respiratory chain. Promoting the differentiation of brown fat precursor cells and the browning of white fat have become a research hotspot for the treatment of obesity and associated metabolic diseases. Several secreted factors and a number of small molecules have been found to promote brown adipogenesis. Here we report that a single small-molecule compound, RepSox, is sufficient to induce adipogenesis from mouse embryonic fibroblasts (MEFs) in fibroblast culture medium. RepSox is an inhibitor of the transforming growth factor-beta receptor I (TGF-ß-RI), other inhibitors of TGF-ß pathway such as SB431542, LY2157299, A83-01, and Tranilast are also effective in inducing adipogenesis from MEFs. These adipocytes express brown adipocyte-specific transcription factors and thermogenesis genes, and contain a large number of mitochondria and have a high level of mitochondrial respiratory activity. More interestingly, RepSox has also been found to promote the differentiation of the brown fat precursor cells and induce browning of the white fat precursor cells. These findings suggest that inhibitors of TGF-ß signaling pathway might be developed as new therapeutics for obesity and type 2 diabetes.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Adipogenia/genética , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL
14.
Cells ; 8(6)2019 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-31234575

RESUMO

Induced brown adipocytes (also referred to as beige cells) execute thermogenesis, as do the classical adipocytes by consuming stored lipids, being related to metabolic homeostasis. Treatment of phytochemicals, including berberine (BBR), was reported to induce conversion from white adipocytes to beige cells. In this study, results of microRNA (miRNA)-seq analyses revealed a decrease in miR-92a, of which the transcription is driven by the c13orf25 promoter in BBR-treated 3T3-L1 cells. BBR treatment manipulated the expressions of SP1 and MYC, in turn, reducing the activity of the c13orf25 promoter. A decrease in miR-92a led to an increase in RNA-binding motif protein 4a (RBM4a) expression, which facilitated the beige adipogenesis. Overexpression of miR-92a or depletion of RBM4a reversely interfered with the impact of BBR treatment on the beige adipogenic signatures, gene expressions, and splicing events in 3T3-L1 cells. Our findings demonstrated that BBR treatment enhanced beige adipogenesis of 3T3-L1 cells through transcription-coupled post-transcriptional regulation.


Assuntos
Adipócitos Bege/metabolismo , Adipogenia/genética , Berberina/farmacologia , Transcrição Genética , Células 3T3-L1 , Adipócitos Bege/efeitos dos fármacos , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipogenia/efeitos dos fármacos , Animais , Sequência de Bases , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Fases de Leitura Aberta/genética , Regiões Promotoras Genéticas/genética , Processamento de RNA/efeitos dos fármacos , Processamento de RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcrição Genética/efeitos dos fármacos
15.
Biochem Pharmacol ; 167: 76-85, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31251940

RESUMO

Mitochondrial biogenesis is a key feature of energy expenditure and organismal energy balance. Genetic deletion of PARP1 or PARP2 was shown to induce mitochondrial biogenesis and energy expenditure. In line with that, PARP inhibitors were shown to induce energy expenditure in skeletal muscle. We aimed to investigate whether pharmacological inhibition of PARPs induces brown or beige adipocyte differentiation. SVF fraction of human pericardial adipose tissue was isolated and human adipose-derived mesenchymal stem cells (hADMSCs) were differentiated to white and beige adipocytes. A subset of hADMSCs were differentiated to white adipocytes in the presence of Olaparib, a potent PARP inhibitor currently in clinical use, to induce browning. Olaparib induced morphological changes (smaller lipid droplets) in white adipocytes that is a feature of brown/beige adipocytes. Furthermore, Olaparib induced mitochondrial biogenesis in white adipocytes and enhanced UCP1 expression. We showed that Olaparib treatment inhibited nuclear and cytosolic PAR formation, induced NAD+/NADH ratio and consequently boosted SIRT1 and AMPK activity and the downstream transcriptional program leading to increases in OXPHOS. Olaparib treatment did not induce the expression of beige adipocyte markers in white adipocytes, suggesting the formation of brown or brown-like adipocytes. PARP1, PARP2 and tankyrases are key players in the formation of white adipose tissue. Hereby, we show that PARP inhibition induces the transdifferentiation of white adipocytes to brown-like adipocytes suggesting that PARP activity could be a determinant of the differentiation of these adipocyte lineages.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Brancos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos
16.
Cell Biochem Funct ; 37(5): 377-384, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31215681

RESUMO

Dietary vitamin A status affects energy metabolism. The present study explored the effect of all-trans retinoic acid (ATRA) on the expression levels of molecules and metabolites of brown adipocytes. Chronic ATRA treatment was initiated during the early stage (days 0-8) or late stage (days 8-12) of adipogenesis. Treatment with ATRA during the early and late stage of adipogenesis resulted in an increase in the expression level of Ucp1 and Cidea, genes highly expressed in brown adipocytes, on day 8 and day 12, respectively, whereas expression of Pgc-1α, another gene expressed during brown adipogenesis, was unaffected by ATRA. Non-targeted metabolomic analyses indicated that the pathways related to the glucose metabolism were affected by ATRA, irrespective of the differentiation stage. Cellular levels of glucose 6-phosphate, fructose 6-phosphate, citric acid, and succinic acid decreased after ATRA treatment on days 8 and 12. In contrast, glucose level was higher in ATRA-treated cells on day 8, but it was lower on day 12. ATRA decreased the cellular level of aconitic acid, fumaric acid, and malic acid on day 12 but not on day 8. Furthermore, ATRA increased the expression level of Hxk2 and downregulated the expressions of G6pdh and Pfkl/Pfkp on day 8 but not on day 12. Together, the results indicate that the chronic treatment with ATRA stimulated the formation of activated brown adipocytes, eventually leading to alterations in the levels of cellular metabolites related to glucose metabolism. SIGNIFICANCE OF THE STUDY: Significance of the study treatment with all-trans retinoic acid (ATRA) during the early and late stage of adipogenesis increased the expression of Ucp1 and Cidea, genes highly expressed in brown adipocytes, on day 8 and day 12. Cellular levels of glucose 6-phosphate, fructose 6-phosphate, citric acid, and succinic acid decreased after ATRA treatment on days 8 and 12. In contrast, glucose level was higher in ATRA-treated cells on day 8, but it was lower on day 12. The present results indicate that ATRA stimulated the formation of activated brown adipocytes, eventually leading to alterations in the levels of cellular metabolites related to glucose metabolism.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Diferenciação Celular/efeitos dos fármacos , Metabolômica , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Tretinoína/farmacologia , Adipócitos Marrons/citologia , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , RNA/genética , Células-Tronco/citologia , Tretinoína/administração & dosagem
17.
J Biol Chem ; 294(24): 9567-9575, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31048375

RESUMO

Inhibitors of methionine aminopeptidase 2 (MetAP2) have been shown to reduce body weight in obese mice and humans. The target tissue and cellular mechanism of MetAP2 inhibitors, however, have not been extensively examined. Using compounds with diverse chemical scaffolds, we showed that MetAP2 inhibition decreases body weight and fat mass and increases lean mass in the obese mice but not in the lean mice. Obesity is associated with catecholamine resistance and blunted ß-adrenergic receptor signaling activities, which could dampen lipolysis and energy expenditure resulting in weight gain. In the current study, we examined effect of MetAP2 inhibition on brown adipose tissue and brown adipocytes. Norepinephrine increases energy expenditure in brown adipose tissue by providing fatty acid substrate through lipolysis and by increasing expression of uncoupled protein-1 (UCP1). Metabolomic analysis shows that in response to MetAP2 inhibitor treatment, fatty acid metabolites in brown adipose tissue increase transiently and subsequently decrease to basal or below basal levels, suggesting an effect on fatty acid metabolism in this tissue. Treatment of brown adipocytes with MetAP2 inhibitors enhances norepinephrine-induced lipolysis and energy expenditure, and prolongs the activity of norepinephrine to increase ucp1 gene expression and energy expenditure in norepinephrine-desensitized brown adipocytes. In summary, we showed that the anti-obesity activity of MetAP2 inhibitors can be mediated, at least in part, through direct action on brown adipocytes by enhancing ß-adrenergic-signaling-stimulated activities.


Assuntos
Adipócitos Marrons/fisiologia , Aminopeptidases/antagonistas & inibidores , Peso Corporal/efeitos dos fármacos , Clorobenzenos/farmacologia , Metabolismo Energético/efeitos dos fármacos , Metaloendopeptidases/antagonistas & inibidores , Obesidade/prevenção & controle , Adipócitos Marrons/citologia , Adipócitos Marrons/efeitos dos fármacos , Animais , Humanos , Lipólise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Ratos , Transdução de Sinais , Termogênese
18.
Mar Drugs ; 17(5)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083362

RESUMO

Obesity is a complex disease resulting in several metabolic co-morbidities and is increasing at epidemic rates. The marine environment is an interesting resource of novel compounds and in particular cyanobacteria are well known for their capacity to produce novel secondary metabolites. In this work, we explored the potential of cyanobacteria for the production of compounds with relevant activities towards metabolic diseases using a blend of target-based, phenotypic and zebrafish assays as whole small animal models. A total of 46 cyanobacterial strains were grown and biomass fractionated, yielding in total 263 fractions. Bioactivities related to metabolic function were tested in different in vitro and in vivo models. Studying adipogenic and thermogenic gene expression in brown adipocytes, lipid metabolism and glucose uptake in hepatocytes, as well as lipid metabolism in zebrafish larvae, we identified 66 (25%) active fractions. This together with metabolite profiling and the evaluation of toxicity allowed the identification of 18 (7%) fractions with promising bioactivity towards different aspects of metabolic disease. Among those, we identified several known compounds, such as eryloside T, leptosin F, pheophorbide A, phaeophytin A, chlorophyll A, present as minor peaks. Those compounds were previously not described to have bioactivities in metabolic regulation, and both known or unknown compounds could be responsible for such effects. In summary, we find that cyanobacteria hold a huge repertoire of molecules with specific bioactivities towards metabolic diseases, which needs to be explored in the future.


Assuntos
Fármacos Antiobesidade/farmacologia , Cianobactérias/química , Obesidade/tratamento farmacológico , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/fisiologia , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/toxicidade , Cianobactérias/crescimento & desenvolvimento , Cianobactérias/metabolismo , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , PPAR gama/metabolismo , Testes de Toxicidade , Proteína Desacopladora 1/metabolismo , Peixe-Zebra
19.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939750

RESUMO

Obesity is a major risk for diabetes. Brown adipose tissue (BAT) mediates production of heat while white adipose tissue (WAT) function in the storage of fat. Roles of BAT in the treatment of obesity and related disorders warrants more investigation. Peroxisome proliferator activator receptor gamma (PPAR-γ) is the master regulator of both BAT and WAT adipogenesis and has roles in glucose and fatty acid metabolism. Adipose tissue is the major expression site for PPAR-γ. In this study, the effects of rosiglitazone on the brown adipogenesis and the association of MAPK and PI3K pathways was investigated during the in vitro adipogenic differentiation of telomerase transformed mesenchymal stromal cells (iMSCs). Our data indicate that 2 µM rosiglitazone enhanced adipogenesis by over-expression of PPAR-γ and C/EBP-α. More specifically, brown adipogenesis was enhanced by the upregulation of EBF2 and UCP-1 and evidenced by multilocular fatty droplets morphology of the differentiated adipocytes. We also found that rosiglitazone significantly activated MAPK and PI3K pathways at the maturation stage of differentiation. Overall, the results indicate that rosiglitazone induced overexpression of PPAR-γ that in turn enhanced adipogenesis, particularly browning adipogenesis. This study reports the browning effects of rosiglitazone during the differentiation of iMSCs into adipocytes in association with the activation of MAPK and PI3K signaling pathways.


Assuntos
Adipócitos Marrons/efeitos dos fármacos , Adipogenia , Hipoglicemiantes/farmacologia , Sistema de Sinalização das MAP Quinases , Rosiglitazona/farmacologia , Adipócitos Marrons/citologia , Adipócitos Marrons/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Linhagem Celular , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
20.
Food Funct ; 10(4): 2221-2233, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30950462

RESUMO

Zeaxanthin (ZEA), a type of oxygenated carotenoid with strong antioxidant activity, has previously been found to exhibit an anti-lipogenesis effect. In the present study, we investigated the effect of ZEA on brown-like adipocyte formation and mitochondrial biogenesis in 3T3-L1 adipocytes. Brown adipocyte-specific markers, mitochondrial biogenesis and oxidative stress, and the involvement of AMP-activated protein kinase (AMPK) α1 were assessed. ZEA treated adipocytes demonstrated a brown-like pattern, with upregulated expression of uncoupling protein 1 (UCP1) and other brown adipocyte markers. In addition, ZEA intervention induced a dramatic increase in mitochondrial DNA (mtDNA) content and in the mRNA levels of genes associated with mitochondrial biogenesis. Furthermore, ZEA attenuated mitochondrial oxidative damage caused by lipid peroxidation in adipocytes, significantly improved the mitochondrial membrane potential (MMP), and scavenged intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Finally, we concluded that AMPKα1 mediated the ZEA-caused inhibition of lipid accumulation and promotion of brown and beige adipocyte-biomarker expression, as the positive effects of ZEA were diminished by Prkaa1 (AMPKα1) knockdown. These findings demonstrated that ZEA promoted the expression of brown and beige adipogenesis markers and mitochondrial biogenesis, which involved AMPKα1 activation, thus contributing to the anti-obesity effects of ZEA.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Marrons/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Zeaxantinas/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipócitos Bege/efeitos dos fármacos , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Adipogenia , Animais , Biomarcadores/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Biogênese de Organelas
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